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Itk functions to control actin polymerization at the immune synapse through localized activation of Cdc42 and WASP
被引:108
作者:
Labno, CM
Lewis, CM
You, DQ
Leung, DW
Takesono, A
Kamberos, N
Seth, A
Finkelstein, LD
Rosen, MK
Schwartzberg, PL
Burkhardt, JK
机构:
[1] Univ Chicago, Dept Pathol, Chicago, IL 60637 USA
[2] Univ Chicago, Comm Immunol, Chicago, IL 60637 USA
[3] NHGRI, NIH, Bethesda, MD 20892 USA
[4] Mem Sloan Kettering Canc Ctr, Cellular Biochem & Biophys Program, New York, NY 10021 USA
[5] Univ Texas, SW Med Ctr, Dept Biochem, Dallas, TX 75390 USA
关键词:
D O I:
10.1016/j.cub.2003.08.005
中图分类号:
Q5 [生物化学];
Q7 [分子生物学];
学科分类号:
071010 ;
081704 ;
摘要:
Actin polymerization at the immune synapse is required for T cell activation and effector function; however, the relevant regulatory pathways remain poorly understood. We showed previously that binding to antigen presenting cells (APCs) induces localized activation of Cdc42 and Wiskott-Aldrich Syndrome protein (WASP) at the immune synapse [1]. Several lines of evidence suggest that Tec kinases could interact with WASP-dependent actin regulatory processes [2]. Since T cells from Rik-/-, Itk-/-, and Rik-/- X Itk-/- mice have defects in signaling and development [3], we asked whether Itk or Rik function in actin polymerization at the immune synapse. We find that Itk-/- and Rik-/- x Itk-/- T cells are defective in actin polymerization and conjugate formation in response to antigen-pulsed APCs. Itk functions downstream of the TCR, since similar defects were observed upon TCR engagement alone. Using conformation-specific probes, we show that although the recruitment of WASP and Arp2/3 complex to the immune synapse proceeds normally, the localized activation of Cdc42 and WASP is defective. Finally, we find that the defect in Cdc42 activation likely stems from a requirement for Itk in the recruitment of Vav to the immune synapse. Our results identify Itk as a key element of the pathway leading to localized actin polymerization at the immune synapse.
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页码:1619 / 1624
页数:6
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